Matrix Gla protein associates with the organic matrix of bone and cartilage. It is thought to act as an inhibitor of calcification []. Defects in MGP are the cause of Keutel syndrome (KS). KS is an autosomal recessive disorder characterised by abnormal cartilage calcification, peripheral pulmonary stenosis neural hearing loss and midfacial hypoplasia [].
This superfamily represents a structural domain with an irregular fold that is found in a subset of coagulation factors, where it forms part of the Gla region.The GLA (gamma-carboxyglutamic acid-rich) domain contains glutamate residues that have been post-translationally modified by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla) [, , ]. All glutamic acid (Glu) residues present in the GLA domain are potential carboxylation sites; in coagulation proteins, all Gu residues are modified to Gla, while in osteocalcin and matrix Gla proteins only some Glu residues are modified to Gla. The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif []is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase.The 3D structure of the GLA domain has been solved [, ]. Calcium ions induce conformational changes in the GLA domain that and are necessary for the proper folding of the GLA domain. A common structural feature of functional GLA domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane [].
Bone gamma-carboxyglutamic acid protein (BGP), also known as osteocalcin, and matrix gamma-carboxyglutamic acid protein (MGP) are the only vitamin K-dependent proteins that have been isolated from bone. MGP is a small protein found in bone, dentin and cartilage. It contains five gamma-carboxyglutamic acid (Gla) residues (formed by post-translational modification of glutamic acid by vitamin K-dependent carboxylase) and a single disulphide bond. BGP is a 49 residue protein found in bone. It contains three Gla residues and a single disulphide bond. There is little similarity between these vitamin K-dependent bone proteins and the blood coagulation proteins, though they are believed to have diverged from a common ancestor [].
The GLA (gamma-carboxyglutamic acid-rich) domain contains glutamate residues that have been post-translationally modified by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla) [, , ]. All glutamic acid (Glu) residues present in the GLA domain are potential carboxylation sites; in coagulation proteins, all Gu residues are modified to Gla, while in osteocalcin and matrix Gla proteins only some Glu residues are modified to Gla. The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif []is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase.The 3D structure of the GLA domain has been solved [, ]. Calcium ions induce conformational changes in the GLA domain that and are necessary for the proper folding of the GLA domain. A common structural feature of functional GLA domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane []. Proteins known to contain a GLA domain include []:Coagulation factor X []Coagulation factor VII []Coagulation factor IX []Coagulation factor XIV (vitamin K-dependent protein C) []Vitamin K-dependent protein S []Vitamin K-dependent protein Z []ProthrombinTransthyretinOsteocalcin (also known as bone-Gla protein, BGP)Matrix Gla protein (MGP) []Inter-alpha-trypsin inhibitor heavy chain H2Growth arrest-specific protein 6 (Gas-6) []
The GLA (gamma-carboxyglutamic acid-rich) domain contains glutamate residues that have been post-translationally modified by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla) [, , ]. All glutamic acid (Glu) residues present in the GLA domain are potential carboxylation sites; in coagulation proteins, all Gu residues are modified to Gla, while in osteocalcin and matrix Gla proteins only some Glu residues are modified to Gla. The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif []is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase.The 3D structure of the GLA domain has been solved [, ]. Calcium ions induce conformational changes in the GLA domain that and are necessary for the proper folding of the GLA domain. A common structural feature of functional GLA domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane []. Proteins known to contain a GLA domain include []:Coagulation factor X []Coagulation factor VII []Coagulation factor IX []Coagulation factor XIV (vitamin K-dependent protein C) []Vitamin K-dependent protein S []Vitamin K-dependent protein Z []ProthrombinTransthyretinOsteocalcin (also known as bone-Gla protein, BGP)Matrix Gla protein (MGP) []Inter-alpha-trypsin inhibitor heavy chain H2Growth arrest-specific protein 6 (Gas-6) []
This family of proteins is found in bacteria and viruses. Proteins in this family are typically between 90 and 105 amino acids in length. There is a conserved GLA sequence motif.
This group of plasma glycoproteins includes coagulation factors VII, IX, and X, and proteins C and Z, which belong to MEROPS peptidase family S1, subfamily S1A (chymotrypsin, clan PA(S)). All but protein Z are peptidases and are involved in blood coagulation. The precursors contain a signal sequence, propeptide, Gla domain, two EGF domains (although sometimes only one is detected by Pfam), and a trypsin domain. Except for protein Z, they are further cleaved between the second EGF domain and the trypsin domain into light and heavy chains, which are connected by a disulphide bond. Glutamic acid residues in the Gla domain undergo vitamin K-dependent carboxylation, allowing this region to bind calcium and membrane phospholipid []. The propeptide region is important in providing a recognition site for the gamma-carboxylase []. Typically one aspartic acid residue in the light chain is post-translationally modified to erythro-beta-hydroxyaspartic acid [, ].
The conantokins are a family of neuroactive peptides found in the venoms of fish-hunting cone snails. They possess a relatively high number of residues (4-5) of the non-standard amino acid gamma-carboxyglutamic acid (Gla), which is generated by the post-translational modification of glutamate (Glu) residues. Conantokins are the only naturally produced peptides known to be N-methyl-D-aspartate (NMDA) receptor antagonists and show therapeutic promise in treating conditions associated with NMDA receptor dysfunction. In animal models they have exhibited anticonvulsant and anti-Parkinsonian properties and have provided neuroprotection within therapeutically acceptable times following transient focal brain ischemia [, , , ].Upon binding of Ca2+ to Gla, conantokin undergoes a conformational transition from a distorted curvilinear 3(10) helix to a linear α-helix. The binding of Ca2+ to conantokin leads to the exposure of a hydrophobic region on the opposite face of the helix []. Conantokins share relatively few sequence elements, which include include sequence identity at the first four residues, homologous positioning of the two most C-terminal Gla residues, and an Arg preceding the most C-terminal Gla [].The conantokin family is currently known to include:Conotoxin G from Conus geographus (Geography cone) (Nubecula geographus).Conantokin-L from Conus lynceus (Lynceus cone) [].Conantokin-R from Conus radiatus (Rayed cone) [].Conantokin-T from Conus tulipa (Fish-hunting cone snail) (Tulip cone) [].Conantokin-P from Conus purpurascens (Purple cone) [].Conantokin-Pr3 from Conus parius (Cone snail) [].Conantokin-Br Conus sulcatus (Sulcate cone) [].
Factor VII (F7) initiates the extrinsic pathway of blood coagulation. It contains an N-terminal Gla domain followed by two epidermal growth factor-like domains (EGF1 and EGF2) and a C-terminal trypsin-like serine protease domain. It can be transformed into active forms (FVIIa) by proteolytic cleavage of the activation peptide located in the connecting region between the EGF2 and the protease domain; this results in the formation of a two-chain FVIIa molecule and a heavy chain held together by a single disulfide bond []. Its first EGF domain (EGF1) binds a calcium ion at its N terminus [].At an injury site, initiation of coagulation begins by exposure of blood to tissue factor (TF) in the extravascular space and formation of the Ca2+-dependent complex between TF and plasma FVIIa. The Ca2+/FVIIa/TF complex formed on the cell surfaces then activates both FX and FIX leading to thrombin generation and fibrin formation []. Mutations in the F7 gene cause Factor VII deficiency (FA7D), the most frequent among rare congenital bleeding disorders [].
Thrombin belongs to the MEROPS peptidase family S1, subfamily S1A.Prothrombin consists of an N-terminal gamma-carboxyglutamate (GLA) domain, two kringle domains, and the S1A peptidase catalytic domain. The cleavage of prothrombin to thrombin is catalysed by the prothrombinase enzyme complex that consists of serine protease factor Xa, cofactor Va, phospholipids and calcium. Prothromin is cleaved by this enzyme into three fragments: fragment 1 (F1) consits of the GLA domain and the first Kringle domain; fragment 2 (F2) consists of the second Kringle domain; and thrombin (peptidase catalytic domain). F1 facilitates calcium-dependent binding of the proenzyme to phospholipid surfaces. F2 interacts with factor Va, and once it is released from prothrombin, it can bind thrombin to influence its function [].Thrombin is a member of the trypsin family of S1 peptidases. It catalyses the preferential cleavage of arginine-lysine bonds, converting fibrinogen to fibrin, and releasing fibrinopeptides A and B. Thrombin can itself cleave the N-terminal fragment (fragment 1) of prothrombin, prior to its activation by factor Xa. Its effects are mediated by the thrombin receptor. Structures of the thrombin A-chain []and B-chain []have been determined. The most conserved portions of the B chain are the active-site residues and adjacent amino acids, the B loop, and the primary substrate-binding region []. The extent of sequence similarity between species and the conservation of many of the functional/structural motifs suggests that, in addition to their role in blood coagulation, vertebrate thrombins may play an important role in the general mechanisms of wound repair [].
The FAS1 (fasciclin-like) domain is an extracellular module of about 140 amino acid residues. It has been suggested that the FAS1 domain represents an ancient cell adhesion domain common to plants and animals []; related FAS1 domains are also found in bacteria [].The crystal structure of FAS1 domains 3 and 4 of fasciclin I from Drosophila melanogaster (Fruit fly) has been determined, revealing a novel domain fold consisting of a seven-stranded beta wedge and at least five alpha helices; two well-ordered N-acetylglucosamine groups attached to a conserved asparagine are located in the interface region between the two FAS1 domains []. Fasciclin I is an insect neural cell adhesion molecule involved in axonal guidance that is attached to the membrane by a GPI-anchored protein.FAS1 domains are present in many secreted and membrane-anchored proteins. These proteins are usually GPI anchored and consist of: (i) a single FAS1 domain, (ii) a tandem array of FAS1 domains, or (iii) FAS1 domain(s) interspersed with other domains. Proteins known to contain a FAS1 domain include:Fasciclin I (4 FAS1 domains).Human TGF-beta induced Ig-H3 (BIgH3) protein (4 FAS1 domains), where the FAS1 domains mediate cell adhesion through an interaction with alpha3/beta1 integrin; mutation in the FAS1 domains result in corneal dystrophy [].Volvox major cell adhesion protein (2 FAS1 domains) [].Arabidopsis fasciclin-like arabinogalactan proteins (2 FAS1 domains) [].Mammalian stabilin protein, a family of fasciclin-like hyaluronan receptor homologues (7 FAS1 domains)[].Human extracellular matrix protein periostin (4 FAS1 domains).Bacterial immunogenic protein MPT70 (1 FAS1 domain) [].The FAS1 domains of both human periostin () and BIgH3 () proteins were found to contain vitamin K-dependent gamma-carboxyglutamate residues []. Gamma-carboxyglutamate residues are more commonly associated with GLA domains (), where they occur through post-translational modification catalysed by the vitamin K-dependent enzyme gamma-glutamylcarboxylase.
The FAS1 (fasciclin-like) domain is an extracellular module of about 140 amino acid residues. It hasbeen suggested that the FAS1 domain represents an ancient cell adhesion domain common to plants and animals []; related FAS1 domains are also found in bacteria [].The crystal structure of FAS1 domains 3 and 4 of fasciclin I from Drosophila melanogaster (Fruit fly) has been determined, revealing a novel domain fold consisting of a seven-stranded beta wedge and at least five alpha helices; two well-ordered N-acetylglucosamine groups attached to a conserved asparagine are located in the interface region between the two FAS1 domains []. Fasciclin I is an insect neural cell adhesion molecule involved in axonal guidance that is attached to the membrane by a GPI-anchored protein.FAS1 domains are present in many secreted and membrane-anchored proteins. These proteins are usually GPI anchored and consist of: (i) a single FAS1 domain, (ii) a tandem array of FAS1 domains, or (iii) FAS1 domain(s) interspersed with other domains. Proteins known to contain a FAS1 domain include:Fasciclin I (4 FAS1 domains).Human TGF-beta induced Ig-H3 (BIgH3) protein (4 FAS1 domains), where the FAS1 domains mediate cell adhesion through an interaction with alpha3/beta1 integrin; mutation in the FAS1 domains result in corneal dystrophy [].Volvox major cell adhesion protein (2 FAS1 domains) [].Arabidopsis fasciclin-like arabinogalactan proteins (2 FAS1 domains) [].Mammalian stabilin protein, a family of fasciclin-like hyaluronan receptor homologues (7 FAS1 domains)[].Human extracellular matrix protein periostin (4 FAS1 domains).Bacterial immunogenic protein MPT70 (1 FAS1 domain) [].The FAS1 domains of both human periostin () and BIgH3 () proteins were found to contain vitamin K-dependent gamma-carboxyglutamate residues []. Gamma-carboxyglutamate residues are more commonly associated with GLA domains (), where they occur through post-translational modification catalysed by the vitamin K-dependent enzyme gamma-glutamylcarboxylase.
